Pharmaceutical composition based on macrolides for topical application in ophthalmology

ABSTRACT

The invention relates to a pharmaceutical composition for preventing and/or treating eye infections, which is to be used by local application. It is in particular directed towards such a composition which is in the form of an eye lotion which can be distributed by drops, in which an antibiotic of the macrolide class, such as azithromycin, is in solution in an oily vehicle. This vehicle is, in particular, of the type of product essentially consisting of medium-chain triglycerides in which the alcohol functions of the glycerol are entirely esterified by carboxylic acids made from saturated hydrocarbons, the molecule of which comprises from 5 to 12 carbon atoms. They are preferably linear-chain fatty acids comprising from 8 to 10 carbon atoms, such as caprylic acid or capric acid. The composition is advantageously prepared by dissolving the active agent in the oily vehicle at a temperature not exceeding 70° C.

[0001] The present invention relates to a novel pharmaceuticalcomposition for preventing and treating eye infections, which issuitable for use by local application into the eye. As essential activeprinciple, it comprises an antibiotic of the macrolide family, which itproposes to provide in the pharmaceutical form of an eye lotion, whichcan be distributed drop by drop.

[0002] It has already been known for a long time that macrolides areantibiotics which are particularly effective, including against eyeinfections. They are compounds of natural or more or less syntheticorigin, the formula of which comprises a heterocycle which integrates alactone function, generally associated with saccharide groups.

[0003] The basic example of macrolides is erythromycin, in which theheterocycle with a lactone function of the molecule already has 14ring-members. Antibiotic efficacy has been verified not only forerythromycin itself, but also for many compounds which derive from itsstructure through various substituents on the main ring. In thisrespect, mention may be made of clarithromycin, roxithromycin anddirithromycin, for 14-membered rings, but also compounds such asspiramycin or josamycin, in which the cyclization coupling twosubstituents produces a 16-membered lactone ring.

[0004] Azalides represent a more recent group in the macrolide class.They derive from the basic structure of erythromycin by insertion of anintracyclic nitrogen into the ring with a lactone function. The leadingmember of this subclass of antibiotic macrolides is azithromycin,corresponding to N-methyl-11-aza-10-deoxo-10-dihydroerythromycin. Inthis compound, since the hydroxyl groups of positions 11 and 12 of theerythromycin are not substituted, the ring with a lactone functionbecomes a 15-membered ring. It is particularly common in the dihydrateform, which is not at all limiting, however, since the compound mayalso, conventionally, be in the form of any biologically compatiblesalt, as in the case of the other compounds of the class.

[0005] As with all compounds which can be used in ophthalmology, thepharmaceutical industry has worked to make it possible to use macrolidesby local application rather than by general administration and, asregards application into the eye, the eye lotion form immediately comesto mind. However, the attempts in this respect have come up againstdifficulties which the present application aims to resolve. Referencemay, in particular, be made to the document of the prior art consistingof international patent application WO 00/57866 (Insite Vision). Thisdocument recalls general knowledge regarding the properties of mucusmembranes, the diseases and pathogenic agents which fall within theprovince of ophthalmic treatment and the conditions for administrationof antibiotics, and it details various macrolide formulae, focusingmainly on azithromycin and on the conditions for the use thereof. Whileshowing themselves to be anxious to treat eye diseases by localapplication of an azalide, all its inventors were able to do in thisregard was to propose providing the azalide in question in the form of asuspension in water to which a suspending polymer has been added. Thesame criticism is to be made with respect to the compositions in theform of azithromycin suspensions which are described in European patentapplication EP 0925789 (Pfizer).

[0006] The present invention makes it possible to avoid the drawbackswhich result therefrom, in particular from the point of view of therisks of irritation of the mucus membranes of the eye and of the cornea.It is also directed towards, more generally, improving the conditions ofuse of the antibiotic compounds of the macrolide family in the usesthereof in ophthalmology. Thus, facilitating the penetration of theactive agent into the cornea and the connective tissues of the eye,improving the retention thereof and the persistence time, ensuring that,at the concentration required as a function of the active dose to beadministered at each instillation, the product does not cause any eyeirritation, decreasing the number of daily instillations and theduration of the treatment and, generally, more fully satisfying thevarious requirements of medical practice, including while preserving theadvantages of local administration, are among the intentions of thepresent invention. From this point of view, an objective of theinvention is also, in particular, to ensure that the treatment isconvenient, to facilitate administration of the composition and to avoidany blurred vision which may appear subsequent to topical application.The invention is also directed towards improving the conditions forindustrial production of the medicinal products, in particular withregard to costs, and also the shelf life of the product before use.

[0007] Given these objectives, and others which may be more clearlyunderstood from the remainder of the present description, the inventionproposes a pharmaceutical composition suitable for the treatment of eyeinfections by local application, characterized in that it is in the formof an eye lotion containing, as therapeutically active agent, anantibiotic compound of the macrolide class in solution in an oilyvehicle.

[0008] It applies especially advantageously to azalides, and moreparticularly to azithromycin. The latter compound currently appears tobe the best for the purpose of the invention. Consequently, all theparticularities of the invention which will be specified hereafter, willbe so, unless otherwise indicated, accepting that the active principlefor which they are most suitable from the industrial point of view isazithromycin, where appropriate as the standard compound of the azalideclass.

[0009] The use of an oily vehicle rather than an aqueous medium, as hasbeen proposed to date, makes it possible to ensure complete dissolutionof the active principle at useful concentrations. A liquid is obtainedwhich is a true solution, in regard of which it is distinguished from asuspension, as fine as the particles in suspension might be, even thoughthe solution may have very variable viscosities. In addition, whateverthe technique among those which it has been possible to envisage fordissolving macrolides in various media, problems of instability of thesolution, easily envisaged as being particularly essential forcompositions intended to be used by local application into the eye, andalso as representing a bridle to an industrialization in goodconditions, are encountered, in particular in the case of azalides.

[0010] One of the main advantages in having a true solution lies in thefact that the active principle is then applied homogeneously over theentire surface of the eye, whereas, in the case of a suspension, thereis uneven contact of the particles of active compound on the eye. Inaddition, azalides are virtually insoluble in water, and also in tears,and solid particles thereof are therefore more readily removed from theeye by the tears, hence a short persistence time for compositions in theform of aqueous suspensions.

[0011] In combination with the complete solubilization of the macrolidein the vehicle according to the invention, the properties inherent tothe oily nature of the vehicle also contribute to increasing thepersistence time of the composition in the eye. Specifically, an oilyfilm forms over the surface of the eye, which is less readily removed bythe tears than in the case of an aqueous composition.

[0012] The formulation of the composition according to the invention inthe form of an oily eye lotion also has other advantages. In particular,it engenders virtually no blurred vision, contrary to what should beexpected of a composition which, moreover, has the advantage of animproved persistence time due to the oily vehicle. Now, it is known, forexample, that other pharmaceutical forms commonly used for topicalapplication in ophthalmology, such as ointments and creams, causeblurred vision for a relatively long period of time afteradministration.

[0013] The invention also relates to a process for preparing apharmaceutical composition suitable for local application inophthalmology, characterized in that it consists in dissolving theantibiotic compound in an oily vehicle, advantageously in the absence ofother constituents, such as those known to be used in other contexts forpromoting the dissolution of a product, also advantageously withoutadding secondary agents, such as various emulsifiers, thickeners orpreserving agents.

[0014] According to the secondary characteristics of the invention, theactive compound is dissolved in the oily vehicle either at normaltemperature, which is generally preferable, if only to simplify theconditions for carrying out the process and to limit the cost thereof,or with slight heating, in particular to a temperature of between 30° C.and 90° C., and preferably of about 50 to 80° C., or more particularlyof about 70° C., in particular when the active compound is azithromycin.In fact, the active compounds specified according to the invention proveto be not only virtually insoluble in water, but also heat-sensitive,and it is important to operate at a temperature at which the activeprinciple remains stable.

[0015] A vehicle of relatively low viscosity will most commonly bechosen, in order to also be able to sterilize the solution, under thesame temperature conditions, during a second step of the process,consisting in operating, for this, by filtration, and preferably at acold temperature, as for the dissolving. One of the major interests ofthe invention is observed here, since the solution may, for example, besterilized simply and effectively through a filtering membrane which haspore sizes of at most equal to 0.2 μm, and preferentially of between 0.1and 0.2 μm, which it would not be possible to envisage in the case ofsuspensions.

[0016] This is particularly advantageous in the present case of theheat-sensitive molecules, namely the macrolides, or more especially theazalides, since the compositions in which they are contained cannot besterilized by conventional means employing heating to high temperatures,for instance by autoclaving. Similarly, exposure to gamma-radiation,another method commonly used for sterilizing compositions comprisingcertain antibiotics, causes degradation of macrolides, and it istherefore preferable to avoid this.

[0017] In general, the concentration of the active agent in the oilyvehicle may be very variable, depending on the particular activecompound, within a range from 0.1 to 2% by weight of the total weight.However, as it has been possible to verify most particularly in the caseof azithromycin, the invention has the advantage of producing solutionswhich are stable at relatively high concentrations of active principle,which leads to preference being given, for reasons of treatmentefficacy, to concentrations of between 0.7 and 2%, in particular ofabout 1 to 1.5% by weight of the total weight.

[0018] In the context of the preferred embodiments of the invention, theoily vehicle used as excipient which is the solvent for the antibioticactive compound also corresponds to one or more of the secondarycharacteristics mentioned below, which may advantageously be appliedsimultaneously or in any technically effective combination.

[0019] Thus, the oily vehicle is preferably chosen so as to be a fattyoil which is of plant origin, but which is refined and/or hydrogenatedand has a viscosity at normal temperature of less than 100 mPa.s (i.e.100 cPo). This satisfies not only conditions suitable for eye lotions,as regards convenience of distribution drop by drop, but alsoparticularly advantageous conditions for industrial production.

[0020] It is also desirable for the viscosity of the final compositionto be at least 10 mpa.s at normal temperature, in particular for reasonsof persistence on the cornea of the eye. In practice, the preferredviscosities are between 10 and 50 mPa.s, particularly about 20 to 40mPa.s, at least when the aim is to simplify as much as possible themethod for producing the medicinal product. Specifically, industrialproduction using sterilization carried out cold on the solution of themacrolide in the oil, without requiring the slightest heating, is thenpreferred.

[0021] It is evident that this does not prevent it possibly beinguseful, for particular cases of application, to supplement thepharmaceutical composition obtained by adding thereto a thickenercompatible with the conditions of administration of the final product.For this, those skilled in the art will be able to find, within theindustry, thickeners which they will use under sterile conditions inorder to increase the viscosity without destroying the solution (mentionshould be made, for example, of cetyl acid, stearic acid, or derivativesthereof). A “delayed” effect of gradual and sustained release of theactive principle is obtained by modulating the viscosity of the solutionin this way, without, however, losing sight of the fact that, inaccordance with the invention, it must be possible to instil it easilyin the form of drops.

[0022] Other advantageous particularities of the oily vehicle suitablefor the implementation of the invention are rather of the chemical type.The corresponding requirements are particularly well satisfied by thefatty oils commonly called medium-chain triglycerides. According tostandards imposed by the European pharmacopoeia, these oils areextracted from coconut and consist essentially, for at least 95%, oftriglycerides of the saturated fatty acids caprylic acid and capricacid. They are therefore, in turn, said to consist of caprylic/caprictriglycerides or triglyceryl caprylate/caprate.

[0023] The composition thus obtained by dissolving the macrolide in avehicle consisting of medium-chain triglycerides is particularlysuitable for ophthalmic treatment by local application, since it makesit possible, inter alia, to satisfy one of the objectives of theinvention, namely ensuring that the risk of irritation of the eyetissues by the composition is reduced to a minimum. The “irritation”includes all effects of temporary burning, of stinging or tears, whichmay be caused by the vehicle used in the formulation or by compoundswhich are associated with it. This is all the more important since thepresence of tears in the eyes, as a result of an irritation, increasesthe rate of elimination of the antibiotic composition.

[0024] In the context of the invention, it therefore appears to beentirely advantageous to use medium-chain triglycerides, which have theparticularity of being very well-defined chemically, and of not beingassociated with by-products which may cause irritation by contact withthe eye. In addition, given the solubility of the antibiotic macrolidesused in this oily vehicle, the composition according to the inventionhas the advantage of not requiring the addition of additives, such assuspending polymers, which considerably reduces the risk of irritationof the eye tissue. For the same reason, the oily solvent consisting ofmedium-chain triglycerides is, according to the invention, largelypreferable to lanolin, which may also be mentioned for dissolving themacrolides, but which has the drawback of being irritant for the eye.

[0025] In the context of the implementation of the invention, theadvantageous results of these characteristics of medium-chaintriglycerides are better control of the composition of the formulation,a reduction of the side effects which may be engendered by irritantadditives, and also better control of the industrial production of theeye lotion.

[0026] More generally, in the context of the implementation of theinvention, the oily vehicles are chosen from fatty oils of plant originwhich can be made available industrially and which consist essentially,in particular, of at least 80% (and preferably at least 95%), of fattyacid triglycerides. They are preferably compounds in which the threealcohol functions of the glycerol are esterified by the acid functionsof fatty acids, the latter preferably being carboxylic acids made fromsaturated hydrocarbons. In addition, the oily vehicle used as solventfor the active compound in accordance with the invention isadvantageously selected so that such triglycerides constituting itessentially derive from one or more acids made from hydrocarbons ofmedium molecular weight having a carboxylic acid function at the end ofa linear chain. The acid molecule is therefore preferentially of mediumlength. From this point of view, it in particular comprises from 5 to 12carbon atoms, and preferably from 8 to 10 carbon atoms, which is, inparticular, the case of caprylic acid and capric acid.

[0027] The oily vehicle preferentially used for the formulation of theinvention has a very low degree of unsaturation. Conventionally, thedegree of unsaturation of an oil can be determined by the amount ofhalogen that can be bonded by the multiple bonds. The amount of halogenbonded, expressed in terms of iodine molecules per 100 g of oil, isknown as the iodine number. Thus, the oily vehicle according to theinvention preferably has an iodine number of less than or equal to 1.The oily vehicle preferentially used for the formulation of theinvention has, moreover, a density advantageously between 0.9 and 1, andpreferentially close to 0.95. According to other particularities of theinvention, its refractive index is preferably between 1 and 2,preferentially between 1.3 and 1.5, and in particular about 1.45, andits density is advantageously close to 1, in particular between 0.9 and1.

[0028] According to a preferred embodiment of the invention, the activetherapeutic agent is azithromycin at a concentration preferably between0.7 and 2% by weight, and preferentially between 1 and 1.5% by weight.The oily vehicle according to the invention makes it possible tocompletely solubilize azithromycin at these concentrations, which isparticularly advantageous with respect to the aqueous vehicles. Indeed,while means for solubilizing azithromycin in aqueous compositions, forexample in citric acid/salt compound mixture (as envisaged in Europeanpatent application EP 1 075 837 in the name of SIFI), are conventionallyknown, it has been noted by the present inventors that azithromycin isrelatively unstable in this type of solution. Quite advantageously, itis, on the contrary, very stable in the oily solutions of plant originaccording to the invention.

[0029] According to a particular formulation of the invention, thepharmaceutical composition is preferentially intended to be provided insingle-dose bottles. This is intended to mean a packaging which isdisposable after the first use, containing the amount of product whichcan be used for two instillations, one into each eye. Due to thestability of the compositions of the invention, it is then advantageousnot to add any additive to the solution, and in particular not to addany preserving agent.

[0030] However, according to another embodiment of the invention, thepharmaceutical composition comprises a preserving agent, as has beenindicated above. This solution is generally preferred when the productis packaged in multidose bottles. The preserving agent is preferentiallyphenoxyethanol, phenylethyl alcohol, chlorobutanol, a quaternaryammonium salt, or any other preserving agent suitable for an eye lotion.In the latter case, when the formulation is prepared, the quaternaryammonium compounds, such as benzalkonium chloride, are preferentiallyincorporated while hot, and the concentration thereof preferentiallydoes not exceed 0.01% by weight. Preserving agents of the paraben typeare incorporated in the same way. They are, in particular, methyl and/orpropyl and/or butyl parahydroxybenzoates.

[0031] According to a preferred preparation process of the invention,the pharmaceutical composition is sterilized by filtration,advantageously over a membrane with a porosity of between 0.1 and 0.2μm. This operation may be carried out cold, more exactly at normaltemperature, or with slight heating to a temperature of about 30 to 40°C., or to a temperature which is higher but remains lower than 80° C.,for example a temperature of about 70° C. The latter solution may bepreferred, in particular when the dissolution of the active compound inthe oily vehicle is also performed hot, in which case the sametemperature conditions may be used for the sterilization. However, whenthe viscosity of the oily vehicle chosen allows it, it generally appearsto be preferable to perform the sterilization by filtration at normaltemperature, for reasons of convenience and of cost. Various types ofmembrane may be used for this filtration operation, such as those basedon cellulose acetate, on polyvinylidene fluoride (PVDF), onpolyethersulphone (PES) or on polytetrafluoroethylene (PTFE).

[0032] To complete the description of the characteristics of theinvention, and also that of the advantages and results thereof, someexamples of preparation of the medicinal product according to theinvention, which, of course, are not limiting, will now be considered.The active principle is present in the form of a base, withoutsalification of the amine function. Comparative examples of the efficacyof the medicinal product according to the invention, compared to twoother azithromycin-based medicinal products, are also provided, as is anexample of ocular pharmacokinetics for azithromycin-based compositionsaccording to the invention at various concentrations of activeprinciple.

EXAMPLE 1

[0033] An eye lotion based on azithromycin at 1.5% by weight isprepared, with the centesimal formulation: azithromycin 1.5 gmedium-chain triglycerides Q.S. for 100 g

[0034] The oily vehicle used corresponds to the European pharmacopoeiadefinition for a refined fatty oil containing 95% of medium-chaintriglycerides in which the alcohol functions of the glycerol areentirely esterified by carboxylic acids made from saturatedhydrocarbons, the chain of which is linear and of medium length, namelyessentially capric acid and/or caprylic acid.

[0035] A mass of medium-chain triglycerides (MCTs) corresponding to 99%of its normal final mass is heated to 70° C. in a water bath. Theazithromycin powder is dissolved in the triglycerides with stirring. Themixture is maintained at 70° C. for a few minutes, and then the solutionobtained is left to cool to ambient temperature. The solution is thenadjusted for weight with the MCT, and the mixture is finished off for afew minutes with stirring.

[0036] The azithromycin remains in solution after cooling, and thesolution obtained is clear and limpid. It is subjected to sterilizationtreatment which is performed by filtration. The procedure is carried outat normal temperature. The filtration is carried out in sterilesurroundings, over a filter with a 0.2 μm mesh, made of apolyethersulphone membrane. A true solution is obtained, which does notrequire, as in the case of formulations of macrolides in an aqueousvehicle, the addition of suspending polymers.

[0037] Stability studies, carried out at 25° C. and 60% humidity, and at40° C. and 75% humidity, show that the solution obtained remains stableover time, for a period of more than six months.

EXAMPLE 2

[0038] An eye lotion based on azithromycin at 1% by weight, intended tobe packaged in single-dose bottles, is prepared.

[0039] The centesimal formula thereof is as follows: azithromycin 1 gmedium-chain triglycerides Q.S. for 100 g

[0040] The procedure in Example 1 is carried out in order to prepare theeye lotion of azithromycin in a medium-chain triglyceride vehicle,except that the concentration is taken to 1% by weight of the totalweight of the composition. The solution is sterilized by filtration asin Example 1. For the medium-chain triglyceride fraction selected in thepresent example, the product has a viscosity of 30 mPa.s (30 cPo at 20°C.). It has a density of 0.95. It has a refractive index equal to 1.45.This value is very close to that of tears, which is equal to 1.33 in ahealthy individual. It results therefrom that the risk of causingblurred vision during the instillation of the eye lotion into the eye isminimized.

EXAMPLE 3

[0041] An eye lotion based on azithromycin at 1% by weight, comprising apreserving agent, is prepared. This eye lotion, intended to be packagedin multidose bottles, has the following composition expressed by weightfor 100 g: azithromycin 1.5 g benzalkonium chloride 0.01 g medium-chaintriglycerides Q.S. for 100 g

[0042] A mass of MCT triglycerides corresponding to 99% of its normalfinal mass is heated to 70° C. in a water bath. The azithromycin andbenzalkonium chloride powders are dissolved in the MCT with stirring.The mixture is kept at 70° C. for a few minutes, and is then left tocool to ambient temperature. The solution is then adjusted for weightwith the MCT, and the mixture is finished off for a few minutes withstirring. The solution is then filtered, in sterile surroundings, over a0.2 μm filter of the high flow rate type made of a polyethersulphonemembrane.

EXAMPLE 4

[0043] An eye lotion based on azithromycin at 0.5% by weight, intendedto be packaged in single-dose bottles, is prepared by carrying out theprocedure as described in Example 1.

[0044] The centesimal formula thereof is as follows: azithromycin 0.5 gmedium-chain triglycerides Q.S. for 100 g

[0045] By way of comparison, an aqueous composition of azithromycin at1% by weight is prepared by dissolving azithromycin in hydrochloricacid. The pH of the solution is adjusted to 7.1 withtris(hydroxymethyl)aminomethane.

[0046] The solution is stored in the dark under temperature and humidityconditions of, respectively, 40° C. and 75%. Samples are taken from thesolution at various time intervals and analysed by high pressure liquidchromatography in order to observe the degradation of the azithromycinover time. For the aqueous solution, degradation of the molecule beginsto be seen after approximately four weeks, and this then accelerates toreach approximately 80% of degraded compound after two months.

[0047] On the other hand, as regards the composition according to theinvention, studied under the same conditions, the azithromycin remainsstable even after storage for 6 months. The solution remains limpid andtransparent.

EXAMPLE 5

[0048] An eye lotion based on azithromycin at 0.5% by weight, comprisinga preserving agent, is prepared. This eye lotion, intended to bepackaged in multidose bottles, has the following composition, expressedby weight for 100 g: azithromycin 0.5 g benzalkonium chloride 0.01 gmedium-chain triglycerides Q.S. for 100 g

[0049] A mass of MCT triglycerides corresponding to 99% of its normalfinal mass is heated to 70° C. in a water bath. The azithromycin andbenzalkonium chloride powders are dissolved in the MCT with stirring.The mixture is kept at 70° C. for a few minutes, and is then left tocool to ambient temperature. The solution is then adjusted for weightwith the MCT, and the mixture is finished off for a few minutes withstirring. The solution is then filtered, in sterile surroundings, over a0.2 μm filter of the high flow rate type made of a polyethersulphonemembrane.

EXAMPLE 6

[0050] An eye lotion based on roxithromycin, at a dose of 0.5% byweight, is prepared by carrying out the procedure as in the previousexamples. The composition comprises a preserving agent since it isintended to be packaged in multidose bottles. roxithromycin 0.5 gbenzalkonium chloride 0.01 g medium-chain triglycerides Q.S. for 100 g

EXAMPLE 7

[0051] An eye lotion based on clarithromycin, at a dose of 0.5% byweight, intended to be packaged in multidose bottles, is prepared.

[0052] The centesimal composition is as follows: clarithromycin 0.5 gchlorobutanol 0.5 g medium-chain triglycerides Q.S. for 100 g

[0053] A mass of commercial medium-chain triglycerides (MCTs)corresponding to 99% of its normal final mass is heated to 70° C. in awater bath. The clarithromycin powder is dissolved in the MCT withstirring. The mixture is kept at 70° C. for a few minutes, and is thenleft to cool to a temperature of 40° C. The chlorobutanol is then addedand the stirring is maintained until complete cooling is reached. Theweight is adjusted with the MCT and the mixture is finished off for afew minutes with stirring. The solution is finally filtered, in sterilesurroundings, through a 0.2 μm filtering polyethersulphone membrane.

EXAMPLE 8

[0054] An eye lotion based on erythromycin, containing 0.5% by weight oferythromycin, is prepared by carrying out the procedure as in theprevious example. Since the eye lotion is intended to be packaged insingle-dose bottles, no preserving agent is added.

EXAMPLE 9

[0055] An eye lotion based on erythromycin at 0.5% by weight isprepared, corresponding to the following centesimal composition:erythromycin 0.5 g chlorobutanol 0.5 g medium-chain triglycerides Q.S.for 100 g

[0056] The procedure is carried out as in the previous examples. Thesolution obtained is limpid. It has a viscosity of about 30 mpa.s atnormal temperature. The product is marketed in single-dose bottles fordistribution drop by drop, applied into the eye.

[0057] As a variant, in this example as in the previous ones, theviscosity may be modulated to values possibly ranging, for example, upto 100 mpa.s by adding a thickener which is miscible in the MCT to thesolution.

[0058] Higher viscosities can be produced, but here, it is preferred toconserve sufficient fluidity for the solution to be suitable as an eyelotion and for the formation of the drops not to be hindered.

EXAMPLE 10

[0059] An eye lotion prepared according to Example 2 is subjected topharmacokinetic tests in order to examine the bioavailability of themedicinal product in the eye. The measurements are taken from theconjunctiva, from the cornea and from the tears of the eyes of rabbits,in comparison with two other azithromycin-based preparations. Theazithromycin level is measured several times a day for six days afteradministration of a single initial dose.

[0060] Three formulae are thus tested. The first concerns an oral doseof azithromycin concentrated at 20 mg/kg, administered by taking atablet. The second concerns a dose into the eye of an aqueous suspensionof azithromycin concentrated at 1% by weight, administered locally byinstilling a drop of the suspension at the surface of the rabbit's eye.The third concerns the oily solution prepared in accordance with Example2, which is administered in the same way.

[0061] The results on the conjunctiva show that the first formula,namely the oral dose of azithromycin, does not make it possible toexceed a conjunctival concentration of azithromycin of greater than 0.1μg/g, whereas the other two formulae produce significant levels 24 hoursafter administration, which are 0.55 μg/g for the aqueous formula and0.60 μg/g for the oily formula of the invention. The superiority of thelatter emerges especially with regard to the prolonging of the presenceof a minimum mean azithromycin level. This level is indeed greater than0.25 μg/g (minimum level for eliminating microorganisms) for only oneday for the form in aqueous suspension, whereas, for the oily form (eyelotion prepared according to Example 2), it remains greater than 0.25μg/g over a period of three days.

[0062] Regarding the cornea, the oral dose only becomes detectable after72 hours, to reach 0.25 μg/g after six days. The aqueous suspensionleads to levels of about 3 μg/g one day after instillation, whichdecrease so as to drop to 0.6 μg/g six days after instillation. The oilysolution proves to be clearly superior; the azithromycin concentrationreaches 3.8 μg/g 24 hours after instillation and remains above 1 μg/gsix days later.

[0063] Besides the fact that the azithromycin exhibits very clearcorneal tropism, the formulation of the eye lotion prepared according toExample 2 is particularly suitable for optimal delivery of the activeprinciple in this ocular region. In the case of the cornea, the topicaluse of azithromycin proves to be more effective for rapidly deliveringthe active principle to its site of action.

[0064] Regarding the tests in tears, the lachrymal levels ofazithromycin are still microbiologically significant one day afterinstillation. The lachrymal levels are 1.9 μg/g for the aqueoussuspension and 2.0 μg/g for the oily solution. They are insufficient forthe oral dose, the presence of azithromycin being undetectable in thiscase.

EXAMPLE 11

[0065] The formulations prepared according to Examples 1 and 4 aresubjected to a study of ocular pharmacokinetics in humans.

[0066] The tests consist in instilling a drop of eye lotion onto thesurface of the eye of patients at one or more given moments, and thentaking tear samples from the treated eyes at various time intervals.

[0067] The samples taken are analysed by high pressure liquidchromatography coupled to mass spectrometry, in order to determine theirazithromycin content. The results thus obtained correspond to theconcentration of azithromycin in the tears at each sampling time. It isverified that the concentration of azithromycin in the tears is at leastequal to 0.5 μg/g in order to obtain the desired therapeutic effect.This value corresponds to the minimum inhibitory concentration ofazithromycin generally described as being the minimum concentrationnecessary to obtain therapeutic effectiveness in the eyes, for allsensitive microorganisms. Thus, the concentration of azithromycin andthe persistence time of the composition must be sufficiently high, inrelation to one another, for a dose of antibiotic greater than or equalto the minimum inhibitory concentration (MIC) to be delivered to the eyetissues targeted.

[0068] Lachrymal Kinetics After Administration of a Single Drop of EyeLotion:

[0069] For each formulation, the lachrymal concentration of azithromycinis measured 0.5; 1; 2; 4; 8 and 24 hours after administration of a dropat the surface of the eye.

[0070] For the eye lotion containing 0.5% of azithromycin, theconcentration of azithromycin in the tears is less than 0.85 μg/g, thevalue corresponding to the minimum quantification threshold of the assaymethod, this being for all the samples, including those taken veryearly, within one hour following administration.

[0071] Regarding the eye lotion containing 1.5% of azithromycin, thefollowing lachrymal concentrations are obtained: Time (hours)[Azithromycin]/tears (μg/g) 0.5 8.85 1 4.53 2 2.45 4 1.68 8 0.87 24 0.91

[0072] It may be noted here that azithromycin is still found in thetears, at a level very largely greater than 0.5 μg/g, 24 hours afteradministration of a single dose of eye lotion at 1.5%.

[0073] Satisfactory results were also observed for a concentration ofazithromycin in the eye lotion of 1%, a concentration of azithromycin ofabout 1 to 1.5% thus appearing to be suitable for delivering atherapeutically effective concentration in humans.

[0074] Lachrymal Kinetics After Repeated Administration of the EyeLotion:

[0075] This study consists in assaying azithromycin in the tears, aspreviously, but after administration of several drops of eye lotion atregular time intervals.

[0076] The eye lotion here contains 1.5% of azithromycin. A first dropis administered at time 0, and then another at each of the followingtimes: 12; 24; 48 and 72 hours. Tear samples are taken 72; 96; 120 and144 hours after the first administration.

[0077] The following concentrations of azithromycin are obtained in thetears: Time (hours) [Azithromycin]/tears (μg/g)  72  2.53*  96 2.98 1205.61 144 2.14

[0078] After five successive applications of the 1.5% azithromycinsolution of Example 1, distributed over a period of 3 days (i.e. 72hours), a high concentration of azithromycin is still found in the tears6 days (i.e. 144 hours) after the first administration.

[0079] The above description clearly explains, in particular with theaid of the detailed examples which have just been set out, how theinvention proceeds, in a way which those skilled in the art could notpredict, to achieve the objectives which it set itself. In particular,it clearly emerges from the above results that a limited number ofinstillations of the composition containing 1 or 1.5% of azithromycinaccording to the invention makes it possible to obtain lachrymalconcentrations which are clearly higher than the minimum inhibitoryconcentration over a relatively long period of time and, through thepharmacokinetic profiles obtained in humans, that it is particularlysuitable for treating bacterial eye infections using an administrationregime consisting of a low number of doses.

[0080] The fact that only a small number of instillations are necessaryto obtain sustained delivery in the eye tissues of a therapeuticallyeffective dose of antibiotic offers many advantages, in particular ofconvenience of treatment, and of reduction of the risk of the userpossibly developing a sensitization to one of the constituents of thecomposition. In other words, the shorter the duration of the treatmentand the more limited the number of the instillations, the more reducedthe risk of reaction/irritation of the eye. The topical use has theadvantage of being potentially effective against microorganisms as soonas the dose is applied, unlike the use of an oral form. In addition, theoily formulation makes it possible to obtain lachrymal, conjunctival andcorneal levels greater than those obtained using aqueous suspensions.

[0081] These advantages in antibiotic efficacy in the treatment of eyediseases add to those which are rather related to the physical form ofsolution, as distinct from the known suspensions, or to the conditionsfor production, in particular regarding the convenience ofsterilization. It will also be noted that the invention lends itself tousing the active compounds of the macrolide family in the form of theirbase rather than in the salt form, which would be unavoidable for anaqueous solution, to which buffers for adjusting the pH would then haveto be added.

[0082] Finally, the use of the fatty acid triglycerides according to theinvention is particularly advantageous in the context of use by localapplication onto the eye tissues, since it makes it possible to obtain asignificant time of persistence on the surface of the eye, while at thesame time maintaining a risk of inflammatory reaction reduced to aminimum, due to the well-defined chemical composition of the fatty acidtriglycerides and to their good capacity for solubilizing all of theactive compound without, however, requiring the addition of furthercompounds.

1. Pharmaceutical composition for treating eye infections by localapplication, characterized in that it is in the form of an eye lotioncontaining, as therapeutically active agent, an antibiotic compound ofthe macrolide class, chosen in particular from azalides, in solution inan oily vehicle.
 2. Pharmaceutical composition according to claim 1,characterized in that said oily vehicle is a fatty oil of plant originacknowledged to be physiologically compatible and consisting essentiallyof fatty acid triglycerides.
 3. Pharmaceutical composition according toclaim 2, characterized in that said oily vehicle consists essentially oftriglycerides of carboxylic acids made from saturated hydrocarbonscomprising a linear chain of medium length, essentially of fatty acidtriglycerides the molecule of which comprises from 5 to 12 carbon atoms,and preferably from 8 to 10 carbon atoms, such as caprylic acid and/orcapric acid.
 4. Pharmaceutical composition according to any one of thepreceding claims, characterized in that said oily vehicle has aviscosity of at least 10 mPa.s and of at most 100 mPa.s at normaltemperature, said viscosity in particular being between 10 and 50 mPa.s,and more particularly about 20 to 40 mPa.s, and in that said oilyvehicle has a density close to 1, in particular between 0.9 and
 1. 5.Pharmaceutical composition according to any one of the preceding claims,characterized in that said oily vehicle has a refractive index ofbetween 1 and 2, preferentially of between 1.3 and 1.5, in particular ofabout 1.45.
 6. Pharmaceutical composition according to any one of thepreceding claims, characterized in that it is provided in single-dosebottles.
 7. Composition according to any one of claims 1 to 10,characterized in that said therapeutically active agent is azithromycin,at a concentration of advantageously between 0.7 and 2% by weight, andpreferentially between 1 and 1.5% by weight.
 8. Process for preparing apharmaceutical eye lotion composition suitable for local application inophthalmology, characterized in that it consists in dissolving anantibiotic compound of the macrolide class, and more particularly anazalide such as azithromycin, in an oily vehicle advantageously of plantorigin and/or consisting of triglycerides, essentially of triglyceridesof fatty acids comprising a linear chain of medium length.
 9. Processaccording to claim 8, characterized in that said pharmaceuticalcomposition is sterilized by filtration through a filtering membranewith a pore size at most equal to 0.2 μm, preferably at normaltemperature, optionally with slight heating to a temperature remainingbelow 80° C.
 10. Pharmaceutical composition in the form of an eyelotion, for treating eye infections by local application, characterizedin that it contains, as therapeutically active agent, azithromycin insolution in an oily vehicle, at a concentration of between 1 and 1.5% byweight of the total weight, said oily vehicle consisting essentially oftriglycerides of carboxylic acids made from saturated hydrocarbonscomprising a linear chain of medium length, in particular of acids suchas caprylic acid and/or capric acid.
 11. Use of azithromycin in the formof a base, and dissolved in an oily vehicle, for preparing an eye lotionsuitable for the treatment of eye infections by local application ontothe eye.
 10. Pharmaceutical composition in the form of an eye lotion,for treating eye infections by local application, characterized in thatit contains, as therapeutically active agent, azithromycin in solutionin an oily vehicle, at a concentration of between 1 and 1.5% by weightof the total weight, said oily vehicle consisting essentially oftriglycerides of carboxylic acids made from saturated hydrocarbonscomprising a linear chain of medium length, in particular of acids suchas caprylic acid and/or capric acid.
 11. Use of azithromycin in the formof a base, and dissolved in an oily vehicle, for manufacturing an eyelotion suitable for the treatment of eye infections by local applicationonto the eye.